Bleeding problems are common in newborn infants, particularly premature infants. Coagulation factor activities follow a gestational age dependent pattern of development. A number of coagulation factor activities including prothrombin are significantly below adult levels in normal newborn infants with more severe deficiencies in premature infants. A chronically catheterized fetal lamb model was found to have a gestational age dependent pattern of blood coagulation factor development during the last trimestey of gestation that is similar to the human. For example, prothrombin activity in the fetal lamb and human follow a similar developmental pattern which is common to a number of other coagulation factors including fibrinogen, factor VII, IX and X. Hypoxia impairs and both glucocorticoids and probably insulin accelerate the development of prothrombin and other clotting factor activities during fetal and early neonatal life. The regulatory mechanisms controlling the levels of prothrombin during normal gestation and the sites of action of the hormones and physiologic stresses on these mechanisms are unknown. This project proposes to examine regulatory mechanisms by addressing the following questions: 1) Are there quantitative differences in prothrombin mRNA concentration during fetal and neonatal development? 2) Are there differences in the rates of transcription of prothrombin mRNA from DNA during fetal and early neonatal development? 3) Are there differences in the rates of translation of prothrombin mRNA during fetal and neonatal development? 4) Are there differences in the proteins synthesized from prothrombin mRNA during fetal and early neonatal development? 5) Are there differences in the post-translational processing of prothrombin peptides during fetal and early neonatal development? 6) Are there differences in the in vivo half-life of plasma prothrombin during fetal and early neonatal development? 7) How are the regulatory control mechanisms influenced by hypoxemia, glucocorticoids and insulin? These questions will be addressed using standard molecular and biochemical techniques most of which are currently available in the principal investigator, co-investigator, or consultant's laboratory. These studies should result in a better understanding of the lowered levels of coagulation factor activities in the newborn and perhaps suggest measures for preventing these deficiencies with a reduction of bleeding complications.